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AGENDA

U.S. ENVIRONMENTAL PROTECTION AGENCY (EPA) 

FIFRA SCIENTIFIC ADVISORY PANEL (SAP) 

OPEN MEETING 

December 2-4, 2014

FIFRA SAP WEB SITE http://www.epa.gov/scipoly/sap/ 

DOCKET NUMBER: EPA–HQ–OPP–2014–0614

U.S. ENVIRONMENTAL PROTECTION AGENCY

CONFERENCE CENTER LOBBY LEVEL

ONE POTOMAC YARD (SOUTH BLDG.)

2777 S. CRYSTAL DRIVE, ARLINGTON, VA 22202

Scientific Issues Associated with Integrated Endocrine Bioactivity and Exposure-Based 

Prioritization and Screening 

Please note that all times are approximate (see note at the end of the Agenda).

9:00 A.M. Opening of Meeting and Administrative Procedures – Fred Jenkins, Ph.D.,

Designated Federal Official, Office of Science Coordination and Policy, EPA

9:05 A.M. Introduction and Identification of Panel Members – James McManaman, 

Ph.D., FIFRA Scientific Advisory Panel (SAP) Session Chair

9:10 A.M. Welcome and Opening Remarks – David Dix, Ph.D., Director, Office of 

Science Coordination and Policy (OSCP), EPA

9:20 A.M. Introduction – Steven Knott, Director, Exposure Assessment Coordination and 

Policy Division (EACPD), OSCP, EPA

9:40 A.M. Estrogen Pathway Data and Models – Richard Judson, Ph.D., Office of 

Research and Development (ORD), National Center for Computational 

Toxicology (NCCT), EPA

10:40 A.M. Break

10:55 A.M. Curated Review of Uterotrophic Literature and Comparison to ToxCast 

Estrogen Receptor (ER) Agonist Area Under the Curve (AUC) Data –

Warren Casey, Ph.D., Director, US National Toxicology Program's Interagency 

Center for the Evaluation of Alternative Toxicological Methods (NICEATM)

Day 1

Tuesday, December 2, 2014
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11:25 A.M. Comparison of ToxCast Data and List 1/Tier 1 ER Assays and ER Agonist 

Bioactivity of Endocrine Disruptor Screening Program (EDSP) Universe 

Chemicals – Patience Browne, Ph.D., EACPD, OSCP, EPA

12:00 P.M. Lunch

1:15 P.M. Androgen Pathway Data and Models – Nicole Kleinstreuer, Ph.D., ORD, 

NCCT, EPA

1:45 P.M. Androgen Receptor (AR) Interpretation and Application – Patience Browne, 

Ph.D., EACPD, OSCP, EPA

2:05 P.M. Break

2:20 P.M. High Throughput Exposure; Toxicokinetics/Dosimetry – John Wambaugh, 

Ph.D., ORD, NCCT, EPA

3:00 P.M. Integrated (RTK) Bioactivity Exposure Ranking (IBER), Modeling 

Uncertainty – Richard Judson, Ph.D., ORD, NCCT, EPA

3:20 P.M. IBER Interpretation and Application – Patience Browne, Ph.D., EACPD, 

OSCP, EPA

3:30 P.M. Adjourn 
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9:00 A.M. Opening of Meeting and Administrative Procedures – Fred Jenkins, Ph.D.,

Designated Federal Official, Office of Science Coordination and Policy, EPA

9:05 A.M. Introduction and Identification of Panel Members – James McManaman, 

Ph.D., FIFRA Scientific Advisory Panel Session Chair

9:10 A.M. Future Directions – Steven Knott, Director, Exposure Assessment Coordination 

and Policy Division (EACPD), OSCP, EPA

9:30 A.M. Public Comments

10:30 A.M Break

10:40 A.M. Public Comments (Cont’d)

12:00 P.M. Lunch

1:15 P.M. Charge to Panel

1.EPA’s proposed approach for quantifying a chemical’s potential estrogen bioactivity is based 

on a computational model integrating data from 18 high throughput ToxCast

assays measuring several endpoints along the estrogen receptor (ER) signaling

pathway. The computational model outputs are expressed as area under the curve

(AUC) scores for ER agonist (R1) and antagonist (R2) bioactivity. Before routinely

using the ER computational model in the Endocrine Disruptor Screening Program

(EDSP) framework, EPA is reviewing the scientific strengths and limitations of the ER

model described in the white paper to: i) prioritize chemicals for further EDSP screening

and testing based on estimated bioactivity, ii) contribute to the weight of evidence

evaluation of a chemical’s potential bioactivity, and iii) substitute for specific endpoints in

the EDSP Tier 1 battery. Please address the following charge questions relevant to

Section 2 of the white paper and estrogen bioactivity:

Charge Question 1a. How clearly has EPA described the computational tools in Section 2.1 

(i.e., high throughput assays and models) used to estimate ER agonist and antagonist

bioactivity?

2:15 P.M. Charge to Panel

Day 2

Wednesday December 3, 2014
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Charge Question 1b. What are strengths and limitations of the ER AUC model’s ability to 

identify reference chemicals that include a variety of structures and have a wide range of

in vitro ER bioactivities?

3:15 P.M. Break

3:30 P.M. Charge to Panel

Charge Question 1c. EPA used data from published in vivo studies that are methodologically

consistent with EDSP Tier 1 guidelines to evaluate concordance between ER AUC model scores 

of in vitro bioactivity, and the in vivo uterotrophic response studies (Section 2.2.1). What are 

strengths and limitations of the curation methods and quality standards used for evaluating 

published in vivo studies?

4:30 P.M. Charge to Panel

Charge Question 1d. Based on all the data presented in Section 2 on ER AUC model 

performance including characterization of reference chemicals, and concordance with in vivo

uterotrophic results, what are strengths and limitations of using the ER AUC

Page 2 of 3 model to distinguish and prioritize chemicals based on potential estrogen

bioactivity?

5:30 P.M. Adjourn

9:00 A.M. Opening of Meeting and Administrative Procedures – Fred Jenkins, Ph.D.

Designated Federal Official, Office of Science Coordination and Policy, EPA

9:05 A.M. Introduction and Identification of Panel Members – James McManaman, 

Ph.D., FIFRA SAP Advisory Panel Session Chair

9:10 A.M. Charge to Panel (Cont’d)

Charge Question 1e. Based on all the data presented in Section 2 on ER AUC model 

performance including characterization of reference chemicals, concordance with in vivo

uterotrophic results, and comparison with Tier 1 assay endpoints, what are strengths and 

limitations of the ER AUC model to contribute to the weight of evidence determination of a 

chemical’s potential estrogen bioactivity?

9:55 A.M. Charge to Panel

Day 3

Thursday December 4, 2014
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Charge Question 1f. Based on all the data presented in Section 2 on ER AUC model 

performance including characterization of reference chemicals, concordance with in vivo

uterotrophic results, and comparison with Tier 1 assay endpoints, what are strengths and 

limitations of using the ER AUC model to substitute for EDSP Tier 1 ER binding, ER 

transactivation, or Uterotrophic assays for the purpose of characterizing a chemical’s potential 

estrogen bioactivity?

10:45 A.M. Break

11:00 A.M. Charge to Panel 

2.EPA’s proposed approach for quantifying a chemical’s potential androgen bioactivity is

based on a computational model integrating data from nine high throughput ToxCast

assays measuring several endpoints along the androgen receptor (AR) signaling

pathway. The computational model outputs are expressed as area under the curve

(AUC) scores for AR agonist (R1) and antagonist (R2) bioactivity. Before routinely

using the AR computational models in the EDSP framework, EPA is reviewing the

scientific strengths and limitations of the AR AUC model described in this white paper

to: i) prioritize chemicals for further EDSP screening and testing based on estimated

bioactivity, and ii) contribute to the weight of evidence evaluation of a chemical’s

potential bioactivity. Please address the following charge questions relevant to Section

3 of the white paper and androgen bioactivity:

Charge Question 2a. How clearly has EPA described the computational tools in Section 3.1 

(i.e., high throughput assays and models) used to estimate AR agonist and antagonist bioactivity?

11:30 A.M. Charge to Panel

Charge Question 2b. What are strengths and limitations of the AR AUC model’s ability to 

identify reference chemicals that include a variety of structures and have a wide range of

in vitro AR bioactivities?

12:00 P.M. Lunch

1:15 P.M. Charge to Panel (Cont’d)

Charge Question 2c. EPA plans to use data from published in vivo studies that are 

methodologically consistent with EDSP Tier 1 guidelines to evaluate concordance between AR

Page 3 of 3 AUC model scores of in vitro bioactivity, and the in vivo androgenic and 

antiandrogenic responses (Section 3.2.1). What are strengths and limitations of the

planned curation methods and quality standards for evaluating published in vivo

studies?

2:15 P.M. Charge to Panel
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Charge Question 2d. Based on the data presented in Section 3 on AR AUC model’s 

performance, what are strengths and limitations of using the AR AUC model to distinguish and

prioritize chemicals based on potential androgen bioactivity?

3:15 P.M. Break

3:30 P.M. Charge to Panel

3. For Endocrine Disruptor Screening Program (EDSP) chemicals with ToxCast estrogen 

receptor (ER) and androgen receptor (AR) bioactivity scores (Section 2 and 3), and ExpoCast 

high throughput toxicokinetics and exposure estimates (Sections 4 and 5), the IBER approach 

was used to rank chemicals based on the ratio between the bioactivity dose range, and the 

expected exposure range (Section 6). The IBER approach extends point estimates of 

bioactivity, toxicokinetics, and exposure for a chemical, to distribution ranges based on 

uncertainty and population variability. Chemical rankings are based on the ratio of the lower 

range of the bioactive dose, to the upper range of the exposure estimate. Please address the 

following charge questions relevant to Section 6 of the white paper and the IBER approach:

Charge Question 3a. How clearly has EPA described the computational tools in Section 6 to 

develop IBER values, including modeling uncertainty and population variability?

3:45 P.M. Charge to Panel 

Charge Question 3b. What are strengths and limitations of using the IBER approach to 

prioritize chemicals for further EDSP screening based on the ratio between the ER bioactivity 

dose range, and the expected exposure range?

4:30 P.M. Charge to Panel

Charge Question 3c. What are strengths and limitations of using the IBER approach to 

prioritize chemicals for further EDSP screening based on the ratio between the AR bioactivity 

dose range, and the expected exposure range?

5:15 P.M. Adjourn

Note: Please be advised that agenda times are approximate; when the discussion for one 

topic is completed, discussions for the next topic will begin. For further information, please 

contact the Designated Federal Official for this meeting, Dr. Fred Jenkins, via telephone: 

(202) 564-3327; fax: (202) 564-8382; or email: jenkins.fred@epa.gov.